Specific roles for dendritic cell subsets during initiation and progression of psoriasis

• Published in: EMBO molecular medicine Vol. 6; no. 10; pp. 1312 - 1327
• Main Authors: Glitzner, Elisabeth, Korosec, Ana, Brunner, Patrick M, Drobits, Barbara, Amberg, Nicole, Schonthaler, Helia B, Kopp, Tamara, Wagner, Erwin F, Stingl, Georg, Holcmann, Martin, Sibilia, Maria
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2014; John Wiley & Sons, Inc; EMBO Press; BlackWell Publishing Ltd; Springer Nature
• Subjects: Adjuvants, Immunologic - pharmacology; Aminoquinolines - pharmacology; Analysis; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - metabolism; AP‐1; Bone marrow; Bone Marrow Transplantation; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Development and progression; Disease Progression; EMBO19; EMBO38; Etiology; Experiments; Flow Cytometry; Humans; IL‐23; Inflammation; Interleukin-10 - immunology; Interleukin-10 - metabolism; Interleukin-23 - immunology; Interleukin-23 - metabolism; Langerhans cells; Langerhans Cells - immunology; Langerhans Cells - metabolism; Lymphocytes; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Patients; Phenotypes; plasmacytoid dendritic cells; Proto-Oncogene Proteins c-jun - deficiency; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - immunology; Psoriasis; Psoriasis - genetics; Psoriasis - immunology; Psoriasis - prevention & control; Receptors, Interleukin - immunology; Receptors, Interleukin - metabolism; Research Article; Roles; Signal Transduction - drug effects; Signal Transduction - immunology; Skin - drug effects; Skin - immunology; Skin - pathology; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - immunology; Langerhans cells; IL‐23; AP‐1; plasmacytoid dendritic cells; psoriasis
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201404114

Several subtypes of APCs are found in psoriasis patients, but their involvement in disease pathogenesis is poorly understood. Here, we investigated the contribution of Langerhans cells (LCs) and plasmacytoid DCs (pDCs) in psoriasis. In human psoriatic lesions and in a psoriasis mouse model (DKO* mice), LCs are severely reduced, whereas pDCs are increased. Depletion of pDCs in DKO* mice prior to psoriasis induction resulted in a milder phenotype, whereas depletion during active disease had no effect. In contrast, while depletion of Langerin‐expressing APCs before disease onset had no effect, depletion from diseased mice aggravated psoriasis symptoms. Disease aggravation was due to the absence of LCs, but not other Langerin‐expressing APCs. LCs derived from DKO* mice produced increased IL‐10 levels, suggesting an immunosuppressive function. Moreover, IL‐23 production was high in psoriatic mice and further increased in the absence of LCs. Conversely, pDC depletion resulted in reduced IL‐23 production, and therapeutic inhibition of IL‐23R signaling ameliorated disease symptoms. Therefore, LCs have an anti‐inflammatory role during active psoriatic disease, while pDCs exert an instigatory function during disease initiation. Synopsis Resident epidermal LCs, which are gradually lost from the epidermis in active disease phase psoriasis, are responsible for maintaining a suppressive skin environment by balancing the anti‐inflammatory IL‐10 and pro‐inflammatory IL‐23 axis. Langerhans cells (LCs) are severely reduced and plasmacytoid DCs (pDCs) are increased in human psoriasis as well as in mouse models of psoriasis Depletion of pDCs in mice prior to psoriasis induction results in disease amelioration whereas depletion during active disease has no effect Depletion of LCs during active psoriasis results in disease aggravation whereas depletion before disease initiation has no effect The anti‐inflammatory role of LCs is mediated by direct release of the immunosuppressive cytokine IL‐10 and by preventing excessive IL‐23 accumulation in the skin pDC depletion results in reduced IL‐23 levels and therapeutic inhibition of IL‐23 receptor ameliorates disease symptoms Graphical Abstract Resident epidermal LCs, which are gradually lost from the epidermis in active disease phase psoriasis, are responsible for maintaining a suppressive skin environment by balancing the anti‐inflammatory IL‐10 and pro‐inflammatory IL‐23 axis.